Chapter 16

Nonspecific Defenses of the Host

Immunity

• Immunity - The ability to ward off disease through body defenses

1. Innate immunity or “nonspecific resistance” • Defenses against any pathogen.• Refers to defenses that are present at birth

2. Adaptive immunity or “specific resistance” : • Defenses to a specific pathogen.• Acquired during the lifetime.

• Lack of immunity is called susceptibility.

Host Defenses

Figure 16.1

1. Mechanical Factors

• Skin– Epidermis consists of tightly packed cells – keratinocytes.

– Keratin is a protective protein.

• Mucous membranes– Ciliary escalator:

Microbes trapped in mucus are transported away from the lungs.

• Lacrimal apparatus: – Washes eye

• Saliva: Washes microbes off.

• Urine: Flows out.

• Vaginal secretions: Flow out.

First line of defense

Figure 16.4 (3 of 3)

Figure 16.3

2. Chemical Factors

– Fungistatic fatty acid in sebum

– Low pH (3-5) of skin

– Lysozyme in perspiration, tears, saliva, and tissue fluids

– Low pH (1.2-3.0) of gastric juice

– Low pH (3–5) of vaginal secretions

– Transferrins in blood find iron.

First line of defense

First line of defense 3. Normal Microbiota

– We have about 1013 cells in our bodies and 1014 bacteria, most of which live in the large intestine.

– There are 103–104 microbes per cm2 on the skin (Staphylococcus aureus, Staph. epidermidis, Corynebacteria (diphteroids), Streptococci, Candida, etc.).

– Fill almost all of the available ecological niches in the body.– Produce factors all of which work to destroy other bacteria that compete for

their niche in the body.

– Microbial antagonism/competitive exclusion: Normal microbiota compete with pathogens.

• The resident bacteria can become problematic when they invade spaces in which they were not meant to be.– Staphylococcus living on the skin can gain entry to the body through small

cuts/nicks. – Clostridium difficile, - Some antibiotics, in particular clindamycin, kill some

of the bacteria in our intestinal tract. This causes an overgrowth of C. difficile, which results in pseudomembranous colitis, a rather painful condition wherein the inner lining of the intestine cracks and bleeds.

Second line of defense

1. Defensive cells – Phagocytic white blood cells– Natural killer (NK)cells

2. Inflammation3. Fiver4. Antimicrobial substances in blood

– Complement system– Interferons– Transferins– Antimicrobial peptides

Fluid Systems of the Body

• There are two main fluid systems in the body:– Blood – Lymph.

• The blood and lymph systems are intertwined throughout the body

• They are responsible for transporting the agents of the immune system.

Human blood cells• Erythrocytes - red blood cells

– Transport O2 and CO2

• Platelets– Blood clotting

• White Blood Cells - Leukocytes– Granulocytes

• Neutrophils - phagocytic • Basophils ( Mast cells in tissues) – Histamine• Eosinophils – Kill parasites• Dendritic cells - antigen-presenting cells

– Agranulocytes• Monocytes - Phagocytic as mature macrophages• Lymphocytes:

– Natural killer cells – T cells – B cells (plasma cells)

White Blood Cells - Leukocytes

• Granulocytes• Neutrophils - phagocytic

– Nondividing, short-lived (half-life of 6–8 hours, 1–4 day lifespan), and have a segmented nucleus.

– First on the scene to fight infection.– Chemotaxis (IL-8, INF-γ, C5a).

• Basophils ( Mast cells in tissues) – Histamine– Circulating, store histamine granules. – Active against parasites, participate in allergic reaction

• Eosinophils – Kill parasites– Granules containing chemical mediators, such as histamine and proteins such as

eosinophil peroxidase, RNase, DNases, lipase, plasminogen, and Major Basic Protein– Some phagocytic

• Dendritic cells – Their main function is to process antigen material and present it on the surface

to other cells of the immune system, thus functioning as antigen-presenting cells

» Initiation of adaptive immune response

• Agranulocytes• Monocytes - Phagocytic as mature macrophages

– Promonocytes are made in the bone marrow, after which they are released into the blood and called circulating monocytes, which eventually mature into macrophages (meaning "big eaters", see below).

– Long-lived, depend on mitochondria for energy, and are best at attacking dead cells and pathogens capable of living within cells.

– Fixed macrophages in lungs, liver, and bronchi– The non-fixed macrophages roam the blood vessels and can even

leave them to go to an infection site where they destroy dead tissue and pathogens.

• Lymphocytes: – Natural killer cells move in the blood and lymph to lyses (cause to

burst) cancer cells and virus-infected body cells. » They attach to the glycoproteins on the surfaces of infected cells

and kill them– T cells - Cell- mediated immunity– B cells (plasma cells) - Produce antibodies

White Blood Cells - Leukocytes

• Percentage of each type of white cell in a sample of 100 white blood cells (Leukocytes)

Differential White Cell Count

Neutrophils 60-70%Basophils 0.5-1%

Eosinophils 2-4%

Monocytes 3-8%

Lymphocytes 20-25%

The Concept of Immunity- Recognition

• Host Toll-like receptors (TLRs) - a class of proteins that play a key role in the innate immune system• Membrane-spanning receptors that recognize structurally conserved molecules

derived from microbes– Localized on cell surface

Monocytes/macrophagesB lymphocytesDendritic cells Mast cells Intestinal epithelium

• These receptors are encoded in the germ line of each person. – Once microbes have breached physical barriers such as the skin or intestinal tract mucosa,

they are recognized by TLRs which activates immune cell responses.– TLRs induce cytokines that regulate the intensity and duration of immune responses

• This immunity is passed from generation to generation. – They are set to target both Gram-negative and Gram-positive bacteria.

Second line of defense1. Phagocytosis

• Phago: eat; Cyte: cell• Ingestion of microbes or particles by a cell, performed by phagocytes

• Once a macrophage phagocytizes a cell, it places some of its proteins, called epitopes, on its surface—much like a fighter plane displaying its hits. – These surface markers serve as an alarm to other immune cells.

1. Adherence2. Ingestion3. Formation of a phagosome4. Phagosome-Lysosome fusion5. Digestion6. Formation of a residual body 7. Discharge

Microbial Evasion of Phagocytosis

• Inhibit adherence: M protein, capsules

Streptococcus pyogenes,

S. pneumoniae

• Kill phagocytes: Leukocidins

Staphylococcus aureus

• Lyse phagocytes: Membrane attack complex

Listeria monocytogenes

• Escape phagosome Shigella

• Prevent phagosome-lysosome fusion

HIV

• Survive in phagolysosome Coxiella burnetti

Second line of defense2. Inflammation

• Inflammation is the process by which the body responds to injury or an infection – It is characterized by:

– Redness

– Pain

– Heat

– Swelling (edema)

– Sometimes the loss of function.

• Chemicals Released by Damaged Cells• Histamine Vasodilation, increased permeability of blood

vessels

• Kinins Vasodilation, increased permeability of blood vessels

• Prostaglandins Intensity histamine and kinins effect

• Leukotrienes Increased permeability of blood vessels, phagocytic attachment

Inflammation- Acute inflammation is a short, intense response to infection. 1. Tissue damage

2. Vasodilation and increased permeability of blood vessel

3. Phagocytes migration and phagocytosis

4. Tissue repair

- Chronic inflammation is a prolonged response (it is a disease)- It is associated with a broad spectrum of neurodegenerative diseases of aging - Alzheimer's

disease, Parkinson's disease, amyotrophic lateral sclerosis, and also included are such peripheral conditions as osteoarthritis, rheumatoid arthritis, atherosclerosis, and myocardial infarction.

• Abnormally High Body Temperature– Hypothalamus normally set at 37°C– Gram-negative endotoxin cause phagocytes to release interleukin1

• Hypothalamus releases prostaglandins that reset the hypothalamus to a high temperature

• Body increases rate of metabolism and shivering to raise temperature• When IL-1 is eliminated, body temperature falls.

• Disadvantages of fiver– Tachycardia– Acidosis– Dehydration

Second line of defense 3. Fever

Second line of defense 4. Antimicrobial substances

• The Complement system– Helps or “complements” the ability of antibodies and phagocytic cells to clear

pathogens from an organism – It is part of the innate immune system that is not adaptable and does not

change over the course of an individual's lifetime.– However, it can be recruited and brought into action by the adaptive immune

system. – It consist of over 25 proteins and protein fragments, produced by liver. – Account for about 5% of the globulin fraction of blood serum.– Complement protein are usually designated by letter C, C1- C9– The fragments are activated proteins and are indicated by the lower letters a

and b – C3a and C3b.– Complement proteins act as a cascade– Once is activated, its destructive capabilities usually cease very quickly

– Inherited deficiencies of complement component causing disease

The Complement System

• C serum proteins constantly present in the blood

• Serum proteins activated in a cascade.

Figure 16.9

Membrane Attack Complex (MAC)

1.Classical Pathway

Complement proteins – factors B, D, and PLectines - proteins that bind to carbohydrates. (When macrophages ingest bacteria, viruses, and other foreign matter by phagosytosis, they release chemicals that stimulate the liver to produce lectins).

2. Alternative Pathway 3. Lectin Pathway

Three biochemical pathways activate the complement system:

Some bacteria evade complement

• Capsules prevent C activation

• Surface lipid-carbohydrates prevent membrane attack complex formation

• Enzymatic digestion of C5a

• Interferons (IFNs) - proteins made and released by lymphocytes in

response to the presence of pathogens – alpha-IFN,

– beta-IFN

– gamma-IFN

• The mode of action of -IFN

and -IFN is to induce uninfected

cells to produce antiviral proteins

(AVPs) that prevent viral replication.

• Interferons are host-cell–specific but not virus-specific.

• Gamma-interferon activates neutrophils and macrophages to kill bacteria.

Second line of defense 4. Antimicrobial substances

Second line of defense 4. Antimicrobial substances

• Transferrins are iron-binding proteins found in blood, milk, saliva, and tears.– Inhibit bacterial growth by reducing the amounts of available iron.

– Iron also suppress chemotaxis and phagocytosis

• Antimicrobial peptides (also called host defense peptides) are an evolutionarily conserved component of the innate immune response and are found among all classes of life.– These peptides are potent, broad spectrum antibiotics which demonstrate

potential as novel therapeutic agents.

– Antimicrobial peptides may also have the ability to enhance immunity by functioning as immunomodulators.

Learning objectives• Differentiate between innate and adaptive immunity.• Describe the role of the skin and mucous membranes in innate immunity.• Differentiate physical from chemical factors, and list five examples of each.• Describe the role of normal microbiota in innate resistance.• Classify phagocytic cells, and describe the roles of granulocytes and monocytes.• Define differential white blood cell count.• Define phagocyte and phagocytosis.• Describe the process of phagocytosis, and include the stages of adherence and ingestion.• Identify methods of avoiding destruction by phagocytes.• List the stages of inflammation.• Describe the roles of vasodilation, kinins, prostaglandins, and leukotrienes in

inflammation.• Describe phagocyte migration.• Describe the cause and effects of fever.• List the components of the complement system.• Describe three pathways of activating complement.• Describe three consequences of complement activation.• Define interferons.• Compare and contrast the actions of a-IFN and b-IFN with g-IFN.• Describe the role of transferrins in innate immunity.• Describe the role of antimicrobial peptides in innate immunity.